The rational development of strategies for preventing or treating radiation injury in the central nervous system (CNS) will require a more complete understanding of the fundamental radiobiology of this critical normal tissue. After other types of CNS injury acute cell death is followed by the activation of secondary reactive processes that occur hours to days after the initial damage and contribute to lesion development. In addition, there is the activation of repair/recovery processes involving the induction of genes coding for a variety of protective cytokines. The working hypothesis of this proposal is that a similar scheme applies to the CNS injury induced by radiation. Proposed studies will address the induction of repair/recovery mechanisms and the activation of secondary processes that contribute to injury development. Regarding the activation of protective mechanisms, the focus will be on the transcription factor NF-kB. Radiation-induced activation of NF-kB in the CNS is followed by a refractory period during which the susceptibility of this transcription factor to activation by subsequent irradiation is significantly reduced. An aim of this proposal is to define the mechanisms that regulate radiation-induced NF-kB activation and to determine its significance in the radioresponse of the CNS. Regarding secondary processes, an aim is to define the incidence of oxidative stress in the rat spinal cord after irradiation. To address the significance of oxidative stress in radiation CNS injury, the effects of specific anti-oxidants on radiation-induced myelopathy will be investigated. Finally, mitochondrial function and metabolism will be investigated in primary cell cultures and in the spinal cord after irradiation. The hypothesis to be tested is that mitochondrial damage serves as a source of oxidative stress and contributes to the development of radiation injury. It is anticipated that delineating the secondary events that contribute to tissue injury and the intrinsic protection mechanisms will lead to identification of processes subject to manipulation and thus provide the basis for developing therapies for radiation induced CNS toxicity.